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Melatonin attenuates high fat diet-induced fatty liver disease in rats
Gregorios Hatzis, Panayiotis Ziakas, Nikolaos Kavantzas, Aggeliki Triantafyllou, Panagiotis Sigalas, Ioanna Andreadou, Konstantinos Ioannidis, Stamatios Chatzis, Konstantinos Filis, Alexandros Papalampros, Fragiska Sigala
Gregorios Hatzis, Panayiotis Ziakas, Stamatios Chatzis, Department of Pathophysiology, Athens University School of Medicine, 11527 Athens, Greece
Nikolaos Kavantzas, Department of Pathology, Athens University School of Medicine, 11527 Athens, Greece
Aggeliki Triantafyllou, Department of Biological Chemistry, Athens University School of Medicine, 11527 Athens, Greece
Panagiotis Sigalas, Ioanna Andreadou, Konstantinos Ioannidis, Department of Pharmaceutical Chemistry, Athens University School of Pharmacy, Panepistimiopolis of Zographou, Zografou, 15771 Athens, Greece
Konstantinos Filis, Fragiska Sigala, 1st Department of Propaedeutic Surgery, Athens University School of Medicine, 11527 Athens, Greece
Alexandros Papalampros, 1st Department of Surgery, Athens University School of Medicine, 11527 Athens, Greece
Author contributions: All authors contributed to the scientific acquisition of data and the writing of the final version of the manuscript; Hatzis G conceived of the study, devised its experimental design, coordinated the study, interpret the data, and was a major contributor in the writing of the manuscript; Ziakas P did the statistical analysis and contributed to the interpretation of the data; Kavantzas N did histopathological examinations of the tissue biopsies; Triantafyllou A performed the biochemical tests and the malondialdehyde and glutathione assays; Sigalas P was responsible for the welfare of the animals and the collection and storage of tissues and sera; Andreadou I performed the biochemical tests and the malondialdehyde and glutathione assays; Ioannidis K was responsible for the welfare of the animals and the collection and storage of tissues and sera; Chatzis S was a contributor in writing and revising the manuscript; Filis K was responsible for the welfare of the animals and the collection and storage of tissues and sera; Papalampros A performed invasive procedures on the animals; Sigala F contributed to the conception of the study, performed the invasive procedures, and oversaw the welfare of the animals as well as the collection and storage of tissues and sera.
Supported by Grant from the Special Account for Research Funds (ELKE) of the National and Kapodistrian University of Athens, Greece, ref. 7493
Correspondence to: Dr. Gregorios Hatzis, Associate Professor of Pathophysiology, Department of Pathophysiology, Athens University School of Medicine, 75 Mikras Asias, 11527 Athens, Greece. grhatzis@med.uoa.gr
Telephone: +30-210-7462674 Fax: +30-210-7462664
Received: October 27, 2012
Revised: December 13, 2012
Accepted: January 17, 2013
Published online: April 27, 2013
AIM: To investigate melatonin’s preventive action in oxidative stress in a rat model with high fat diet-induced non-alcoholic fatty liver disease (NAFLD).
METHODS: NAFLD was induced by high fat diet (HFD) in adult, male, Wistar rats, weighing 180-230 g. After acclimatization for one week, they were randomly assigned to 6 experimental groups that comprised animals on regular diet plus 5 or 10 mg/kg melatonin, for 4 or 8 wk; animals on HFD, with or without 5 or 10 mg/kg melatonin, for 4 or 8 wk; and animals on HFD for 8 or 12 wk, with melatonin 10 mg/kg for the last 4 wk. Liver damage was assessed biochemically by the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and histologically. Lipid peroxidation and oxidative stress were assessed by malondialdehyde and glutathione levels in liver tissue. Lipidemic indices and portal vein pressure were also measured.
RESULTS: Compared to rats not receiving melatonin, rats on 5 or 10 mg/kg of melatonin had lower mean liver weight (-5.0 g and -4.9 g) (P < 0.001) and lower liver weight to body weight ratio (-1.0%) (P < 0.001), for the two doses, respectively. All rats fed HFD without melatonin developed severe, grade III, steatosis. Rats on HFD with concurrent use of melatonin showed significantly less steatosis, with grade III steatosis observed in 1 of 29 (3.4%) rats on 10 mg/kg melatonin and in 3 of 27 (11.1%) rats on 5 mg/kg melatonin. Melatonin was ineffective in reversing established steatosis. Melatonin also had no effect on any of the common lipidemic serum markers, the levels of which did not differ significantly among the rats on HFD, irrespective of the use or not of melatonin. Liver cell necrosis was significantly less in rats on HFD receiving melatonin than in those not on melatonin, with the AST levels declining by a mean of 170 U/L (P = 0.01) and 224 U/L (P = 0.001), and the ALT levels declining by a mean of 62.9 U/L (P = 0.01) and 93.4 U/L (P < 0.001), for the 5 and 10 mg/kg melatonin dose, respectively. Melatonin mitigated liver damage due to peroxidation and oxidative stress in liver tissue as indicated by a significant decline in MDA production by 12.7 (P < 0.001) and 12.2 (P < 0.001) μmol/L /mg protein /mg tissue, and a significant increase in glutathione by 20.1 (P = 0.004) and 29.2 (P < 0.001) μmol/L /mg protein /mg tissue, for the 5 and 10 mg/kg melatonin dose, respectively.
CONCLUSION: Melatonin can attenuate oxidative stress, lessen liver damage, and improve liver histology in rats with high fat diet-induced NAFLD, when given concurrently with the diet.
